This project, begun last year, is given to an evaluation of the role of nitric oxide as a potential mediator of the coupling of local cerebral blood flow to local cerebral metabolic and/or functional activities. Having found that the action of 5% C02 to increase cerebral blood flow was unaffected by the intravenous administration of methylarginine in doses up to 100 mg/kg, the possibility was considered that C02 acted on the abluminal side of cerebral vessels and that the inhibitor must therefore cross the blood-brain barrier to block nitric oxide synthase. After demonstrating by direct chemical analysis that methylarginine crosses the barrier relatively slowly, nitroarginine methyl ester, a better candidate for gaining access to brain from plasma was evaluated. This more powerful inhibitor of nitric oxide synthase, also failed to block an increase in cerebral blood flow by 5% C02. Both methylarginine and nitroarginine were then examined for an effect on the increase in local blood flow induced by functional activity. In experiments during which whiskers were repeatedly stroked on one side, neither inhibitor given intravenously reduced the blood flow response in any part of the pathway from brainstem to barrel field of the cortex. Intracisternally administered nitroarginine likewise was without effect in blocking the blood flow response to stroked whiskers. On the basis of the results obtained to date it appears that nitric oxide is unlikely to be a significant mediator of either the action of C02 or of functional activity to increase cerebral blood flow.